Pneumocystis carinii is a microorganism that causes pneumonia in immunocompromised patients. The principal goal of this project is the improvement of both prophylaxis and treatment of P. carinii pneumonia through the development of a drug with high ratio of efficacy to toxicity.The specific aims of this proposal are: (1) to select a set of active, moderately active, and inactive compounds; (2) to generate a preliminary hypothesis to explain activity in terms of chemical structure; (3) to evaluate the hypothesis against other compounds of various activities; (4) to search databases for compounds that fit the hypothesis; (5) to test in vitro the compounds that best fit the hypothesis for activity against P. carinii; and (6) to test in vivo the compounds that show the greatest activity in vitro. Beginning with observed activity values, computer-based methods for elucidating quantitative structure-activity relationships (QSAR) will be used to identify chemical functions (e.g., hydrogen bond donor, hydrophobic group, positive ionizable group), with coordinates in 3-dimensional space, that likely account for anti- Pneumocystis activity. To complete these structural hypotheses, computational molecular modeling will be used to identify substructures (e.g., alkyl, amino, halo) that further effect activity. Compounds that meet the structural criteria for activity will be tested in vitro. The most active compounds will then be tested in vivo under an existing arrangement with National Institutes of Health.